Synthesis of nitrogen heterocycles by intramolecular Michael type of amination via reduction of imines with di-n-butyliodotin hydride (n-Bu2SnIH)

Article abstract of DOI:10.1021/ol990225i

(matrix presented). Novel nitrogen heterocycles were prepared by a one-pot procedure involving the reductive amination of the bifunctional substrates containing an aldehyde and enone groups with di-n-butyliodotin hydride (n-Bu₂SnIH).

Full text of DOI:10.1021/ol990225i

ORGANIC
LETTERS
1
999
Vol. 1, No. 10
579-1581
Synthesis of Nitrogen Heterocycles by
Intramolecular Michael Type of
1
Amination via Reduction of Imines with
Di-n-butyliodotin Hydride (n-Bu SnIH)
2
Toshihiro Suwa, Ikuya Shibata, Keita Nishino, and Akio Baba*
Department of Molecular Chemistry, Graduate School of Engineering,
Osaka UniVersity, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
shibata@ap.chem.eng.osaka-u.ac.jp
Received August 11, 1999
ABSTRACT
Novel nitrogen heterocycles were prepared by a one-pot procedure involving the reductive amination of the bifunctional substrates containing
an aldehyde and enone groups with di-n-butyliodotin hydride (n-Bu SnIH).
2
3
Intramolecular Michael type amination of ω-amino unsatur-
ated ketones where the amine was created by reductive
amination is a good method for the preparation of nitrogen
heterocycles because enones are effective electrophiles with
reported so far. Another problem is that imines are generally
difficult to isolate because of their instability. This problem
could be solved by reductive amination of the aldehyde
moiety in the presence of an enone group. We have been
developing the unique reactivities of the halogen-substituted
1
amine nucleophiles. However, the method has scarcely been
2
4
5a
used to build nitrogen heterocycles. This may result from
tin hydride systems such as n-Bu SnIH and n-Bu SnClH-
HMPA which promote effective reductions of enones and
imines, respectively. In particular, n-Bu SnClH-HMPA
affords effective reductive aminations. In this Letter, we
describe a facile access to functionalized nitrogen hetero-
2
2
5b,c
the difficulty of chemoselectively generating an amine. If
imine-selective reduction was carried out for a substrate
containing both imine and enone functionalities, the 1,4-
addition of the generated amine would provide nitrogen
heterocycles (Scheme 1).
2
5d
(2) Glanzmann, M.; Karalai, C.; Ostersehlt, B.; Shoen, U.; Frese, C.;
Winterfeldt, E. Tetrahedron Lett. 1982, 38, 2805. (b) Godleski, S.; Heacock,
D. J. J. Org. Chem. 1982, 47, 4820. (c) Parker, K. A.; Cohen, I. D.; Babine,
R. E. Tetrahedron Lett. 1984, 33, 3543. (d) Jeon Y. T.; Lee, C.-P.; Mariano,
P. S. J. Am. Chem. Soc. 1991, 113, 8847. (e) Xu, W.; Zhang, X.-M.;
Mariano, P. S. J. Am. Chem. Soc. 1991, 113, 8863.
Scheme 1
(3) Imine reduction, for example: (a) Hutchins, R. O.; Hutchins, M. K.
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: New York, 1991; Vol. 8, p 25. (b) Lane, C. F. Synthesis 1975,
1
35. (c) Gribble, G. W. Chem. Soc. ReV. 1998, 27, 395.
4) Tin hydride reduction, review. Pereyre, M.; Quintard, J.-P.; Rahm,
A. Tin in Organic Synthesis; Butterworths: London, 1987.
5) (a) Kawakami, T.; Miyatake, M.; Shibata, I.; Baba, A.; Matsuda, H.
J. Org. Chem. 1996, 61, 376. (b) Kawakami, T.; Sugimoto, T.; Shibata, I.;
Baba, A.; Matsuda, H.; N. Sonoda. J. Org. Chem. 1995, 60, 2677. (c)
Shibata, I.; Moriuchi-Kawakami, T.; Tanizawa, D.; Suwa, T.; Sugiyama,
E.; Matsuda H.; Baba, A. J. Org. Chem. 1998, 63, 383. (d) Shibata, I.;
Suwa, T.; Sugiyama, E.; Baba, A. Synlett 1998, 1081.
(
However, as far as we know, no imine-selective reductions
in the presence of reducible enone functions have been
(
(1) Shaefer, M.; Draz, K.; Schwarn, M. StereoselectiVe Synthesis;
Helmchen, G., Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds.;
Thieme: Stuttgart, 1987; Vol. 9, p 5588.
1
0.1021/ol990225i CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/15/1999

In accordance with the above results, we applied the imine-
selective reduction to the synthesis of nitrogen heterocycles.
We initially tried to use substrates 7 which contain both
enone and imine groups (Table 2). Whereas imines 7 were
difficult to isolate, they could be prepared in situ. Namely,
the three-component reaction of tin hydride, substrate 5, and
amine 6 was carried out. Starting substrates 5 could be
prepared easily from o-phthalaldehyde with an appropriate
Table 1. Chemoselectivity of Enone vs Imine in the Reduction
with Tin Hydrides
a
Wittig reagent. n-Bu
2
SnClH-HMPA and n-Bu SnIH-
2
HMPA gave the desired isoindoline 8a in 58% and 53%
yields, respectively (entries 1 and 2). Although chlorotin
hydride (n-Bu
was accompanied in 18% yield by the partial reduction of
enone moiety (entry 3). Nonhalogenated tin hydride (n-Bu
SnH) gave 8a in only 8% yield with complicated mixtures
2
SnClH) also gave 8a in 40% yield, product 9
3
-
(
entry 4). The use of a conventional imine-selective reductant
3
b
3
such as NaBH CN under the standard conditions resulted
2
in a low yield of 8a (26%) (entry 5). Interestingly, n-Bu -
SnIH afforded 8a in 64% yield as a sole product (entry 6).7
Thus reductive amination of the formyl moiety in 5 proceeds,
and the resulting tin amide effectively attacks the â-carbon
cycles by highly imine-selective reductions with halogen-
substituted tin hydride.
To investigate the chemoselectivity of the reduction of
enones vs imines with tin hydrides, we initially examined
the competitive reaction of equimolar amounts of enone 1
and imine 2 in THF solvent (Table 1). Tri-n-butyltin hydride
8
of the remaining enone (Scheme 2). Compared with the
Scheme 2
(
(
(
n-Bu
entry 1). In contrast, with chloro-substituted tin hydride
n-Bu SnClH), the reaction proceeded under milder condi-
3
SnH) slowly reduced enone 1 to give 3 predominantly
2
tions, and amine 4 derived from the reduction of imine was
obtained in 30% yield in addition to 3 (entry 2). Interestingly,
iodo-substituted tin hydride (n-Bu SnIH) promoted the
2
predominant formation of 4 (entry 3). The use of penta-
coordinate halogenotin hydride complexes, which have
previously been reported to provide high imine selectivity
over carbonyls, gave 4 effectively (entries 4 and 5). Thus
halogenotin hydride derivatives bear imine selectivity even
in the presence of enones.
results of intermolecular imine-selective reduction in Table
2
1, iodotin hydride (n-Bu SnIH) works especially well for the
5
b,c
9
intramolecular reductive amination. Despite a one-pot
reaction, no products derived from the reduction of enone
or formyl moiety in 5 were obtained.
Table 2. Synthesis of Isoindolines by Reductive Aminationa
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Org. Lett., Vol. 1, No. 10, 1999

2
By using n-Bu SnIH, various aromatic amines could be
used to give isoindoline 8 (entries 7-9). In the case of N-p-
chlorophenyl-substituted substrate 7c, the yield of 8c was
increased up to 82%, where a halogen group on the aromatic
ring was not affected (entry 9). In all cases, the use of excess
Table 3. Synthesis of Piperidinesa
2
n-Bu SnIH did not increase the yield of 8 because of the
increase of the formation of 9.
The halogen substituent of the tin hydride is responsible
for the high imine selectivity. Thus we assume that the tin
halide promotes the formation of an iminium ion as a key
intermediate (Scheme 3). The activated imine thus formed
Scheme 3
aldehyde function in 10 with aniline, followed by the
intramolecular Michael additin of the resulting tin amide,
gave piperidine 12a in 56% yield in the one-pot procedure
(entry 1). Thus, piperidines 12b-d were obtained selectively
in good yields (entries 2-4). In all cases, no side reaction
such as the reduction of enone or aldehyde was observed.
In this way, various nitrogen heterocycles, isoindolines,
and piperidines could be prepared in a one-pot procedure
by the imine-selective reduction of in situ formed bifunctional
substrates bearing imine and enone functionalities.
would be reduced more rapidly than other functionalities such
as starting aldehydes and enones.
Furthermore, after the imine-selective reduction, the result-
ing iodo-substituted tin amide bears adequate nucleophilicity
to attack the remaining enone because noncyclized secondary
amines were not detected in the reaction.
Besides aromatic substrates 5, aliphatic ones were also
applicable for the preparation of nitrogen heterocycles in a
similar manner (Table 3). Thus reductive amination of the
Acknowledgment. This work was financially supported
by a Grant-in-Aid for Scientific Research from the Ministry
of Education, Science and Culture and JSPS Research
Fellowships for Young Scientists. Thanks are due to Mr. H.
Moriguchi, Faculty of Engineering, Osaka University, for
assistance in obtaining HRMS spectra.
(
6) Sawer, A. K.; Brown, J. E.; Hanson, E. L. J. Organomet. Chem.
965, 3, 464.
7) The reaction to give isoindoline 8a was performed as follows. Di-
1
(
n-butyliodotin hydride (n-Bu2SnIH, 1 mmol) was prepared in situ by mixing
dibutyltin dihydride (n-Bu2SnH2, 0.5 mmol) and tin diiodide (n-Bu2SnI2,
.5 mmol) in THF (1 mL) at room temperature. To the solution were added
substrate 5 (1 mmol) and aniline 6 (1 mmol). After the mixture was stirred
at 0 °C for 2 h, MeOH was added, and volatiles were removed under reduced
pressure. The residue was chromatographed on silica gel (hexane/EtOAc
0
Supporting Information Available: Experimental pro-
)
3/1) to afford 8a.
8) Although the possibility of the attack of a free amine to enone is not
1
13
(
cedures and IR, H NMR, C NMR, and HRMS spectra for
a-d and 12a-d. This material is available free of charge
excluded, we think that the more nucleophilic tin amide may play an
important role in the cyclization.
8
(
9) Although the higher selectivity of n-Bu2SnIH than pentacoordinate
via the Internet at http://pubs.acs.org.
tin reagent is not clear yet, we assume the more acidic n-Bu2SnIH works
rather well for the formation of an iminium ion.
OL990225I
Org. Lett., Vol. 1, No. 10, 1999
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